This proposal describes a five year training program for a career as an independent investigator in Pulmonary Medicine. The principal investigator has finished a fellowship in Pulmonary, Allergy and Critical Care Medicine at the University of Pennsylvania, and is currently researching steroid insensitive inflammation in airway smooth muscle (ASM), a tissue that is relevant in asthma and other lung diseases. The short term goal of the studies performed during the term of this mentored award is to delineate some of the molecular mechanisms by which vitamin D decreases inflammation in the airways, as well as to further develop precision cut lung slices as an ex vivo experimental model for airway inflammation. The principal investigator's long term goal is to establish his own independent research program and submit an RO1 application. The central hypothesis of the proposal is novel and states that activation of the vitamin D receptor decreases inflammatory gene expression in the airway by promoting activation of the glucocorticoid receptor and inhibiting activation of transcription factors. The specific aims include: 1) Determining whether vitamin D inhibits inflammatory gene expression in ASM and ex vivo by genomic or nongenomic mechanisms, 2) Defining crosstalk between the vitamin D receptor and the glucocorticoid receptor in inhibition of inflammatory gene expression in ASM and ex vivo, and 3) Determining whether vitamin D is able to inhibit inflammatory gene expression in airway smooth muscle and ex vivo by inhibiting activation of transcription factor nuclear factor kappa B. This project will take place under the mentorship of Dr. Reynold Panettieri, director of the Airways Biology Initiative and an expert in airway smooth muscle biology who has trained twenty five postdoctoral fellows. In addition, the candidate will take advanced coursework and meet regularly an advisory committee of highly regarded physician scientists who will provide sceintific and career advice. The department of Pulmonary, Allergy and Critical Care Medicine at the University of Pennsylvania provides an ideal setting for training physician scientists, and this proposal will give the principal investigator an ideal skill set for a career as an independent investigator. PUBLIC HEALTH RELEVANCE: Patients with steroid insensitive asthma have symptoms of airway obstruction and inflammation despite high doses of inhaled or oral steroids. These patients contribute disproportionally to asthma healthcare costs and morbidity, and present a therapeutic challenge. Understanding how vitamin D inhibits airway inflammation could provide insight into new therapeutic alternatives that could help these patients.